1. Field of the Invention
The invention relates to a process for preparing potassium monoethyl malonate (or the potassium salt of malonic acid monoethyl ester; designated KEM hereafter) by selective saponification of diethyl malonate (or malonic acid diethyl ester; designated DEM hereafter) with potassium hydroxide, the target product being obtained in high purity.
2. Discussion of the Background
KEM is used as a precursor for the syntheses of pharmaceuticals having a quinolone structure. The use for syntheses in the pharmaceutical area, however, requires high product purity. In particular, a significant content of dipotassium malonate (designated DKM hereafter) is undesired.
A synthesis of potassium monoethyl malonate which was described as early as in the last century by van't Hoff (Ber. Dtsch. Chem. Ges. 7, 1572) and which is still currently practiced starts from DEM which is selectively saponified with potassium hydroxide. According to EP 0 720 981 Al, this is performed using equimolar amounts of starting material in an alcoholic medium. However, the sought-after selective saponification is achieved only to an inadequate extent, so that only a target product considerably contaminated with dipotassium malonate (DKM) is obtained. The content of DKM is customarily in the order of magnitude of several % by weight. Removal of the dipotassium malonate from the potassium monoethyl malonate which is necessary for use of the latter as a pharmaceutical precursor is difficult and includes extensive purification operations. A further disadvantage of the known process is the relatively high dilution at which the process must be carried out. The alcohol is used at 19 to 28 times the amount by weight of potassium hydroxide. This large amount of alcohol has an adverse effect on the space-time yield and increases the expense for recovery of the solvent. In the case of the processes mentioned, the amount of alcohol is further increased by the DEM likewise being used in alcoholic solution.
Box et al., Heterocycles, Vol. 32, No. 2, 1991, 245 ff., describe a synthesis of .beta.-lactones and .beta.-lactams, in which KEM is as intermediate. The two starting materials are, as in the process described in EP 0 720 981 Al discussed above, used in equimolar amounts, that is to say each at 100 mmol. The molar ratios of DEM to KOH were calculated incorrectly, however, since 20.225 g of DEM is 126 mmol and is equivalent to 1.26 times the molar amount, based on KOH. If it is further assumed that the potassium hydroxide used had, as is commercially usual, a KOH content of approximately 90% by weight (remainder water), 20.225 g of DEM are actually equivalent to 1.38 times the molar amount, based on KOH (calculated as 100%). Working using molar ratios of 1.26:1 and 1.38:1 showed that although pure KEM containing less than 0.5% by weight of DKM was obtainable by this process, the precipitated KEM was really difficult to filter. In the case of laboratory batches, the filtration time was more than two hours. Such times are prohibitive for production on an industrial scale. In addition, according to Box et al., similar to the process of EP 0720 981 Al cited above, considerable amounts of alcohol are required. Finally, the yields of KEM are not satisfactory either.